Persistent Newborn Pulmonary Hypertension
Persistent Newborn Pulmonary Hypertension
Persistent Newborn Pulmonary Hypertension
Overview
Persistent pulmonary hypertension of the newborn (PPHN) is defined as the failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extrapulmonary shunting of blood. Because a patent foramen ovale and patent ductus arteriosus are normally present early in life, elevated pulmonary vascular resistance in the newborn produces extrapulmonary shunting of blood, leading to severe and potentially unresponsive hypoxemia. With inadequate pulmonary perfusion, neonates are at risk for developing refractory hypoxemia, respiratory distress, and acidosis. Clinically, PPHN is most often recognized in term or near-term neonates, but it can occur, albeit infrequently, in premature neonates.
Types of PPHN
Persistent PPHN can be generally characterized as one of 3 following types: PPHN characterized by abnormally constricted pulmonary vasculature due to lung parenchymal diseases (eg, meconium aspiration syndrome, respiratory distress syndrome, pneumonia; see the image of meconium aspiration below) PPHN characterized by hypoplastic vasculature, as seen in congenital diaphragmatic hernia
PPHN in which the lung has normal parenchyma and remodeled pulmonary vasculature (also known as idiopathic PPNH)
Meconium aspiration. Serial radiographs in a newborn with uncomplicated meconium aspiration. Radiograph obtained shortly after birth shows ill-defined, predominantly perihilar opacities in the lungs; these are more severe on the right than on the left. The lungs are hyperexpanded. The neonate's heart size is within normal limits. The abnormalities on the initial chest radiograph, aside from the presence of an endotracheal tube and an umbilical artery catheter, are identical to those seen in severe cases of transient tachypnea of the newborn. Some clinicians refer to idiopathic PPNH as "black lung" PPNH or "clear lung" PPNH.
Neurologic sequelae
Although most surviving newborns with persistent pulmonary hypertension of the newborn have normal neurodevelopmental outcomes, as many as 25% have significant neurodevelopmental sequelae. Prolonged hyperventilation is associated with an increased prevalence of neurodevelopmental sequelae, especially sensorineural hearing loss.
Etiology
The factors that produce antenatal vascular remodeling are not completely understood. Genetic factors may increase susceptibility to pulmonary hypertension. Strong links between persistent pulmonary hypertension of the newborn (PPHN) and polymorphisms of the carbamoyl phosphate synthase gene have been reported. However, the importance of this finding is uncertain, and further work is needed in this area. Newborn rats exposed in utero to fluoxetine develop pulmonary vascular remodeling, abnormal oxygenation, and higher mortality when compared with vehicle-treated controls. Because selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce pulmonary vascular remodeling in adult models of pulmonary hypertension, these findings highlight the unique nature of fetal pulmonary vascular development.[1] Persistent pulmonary hypertension of the newborn is most commonly associated with 1 of 3 underlying etiologies, as follows: Acute pulmonary vasoconstriction Hypoplasia of the pulmonary vascular bed Idiopathic pulmonary hypertension
Congenital diaphragmatic hernia is an abnormality of diaphragmatic development that allows the abdominal viscera to enter the chest and compress the lung. The oligohydramnios sequence may produce pulmonary hypoplasia and associated persistent pulmonary hypertension of the newborn. A congenital cystic adenomatoid malformation may lead to lung hypoplasia, although persistent pulmonary hypertension of the newborn is rarely associated with this malformation, even if the defect is large.
Epidemiology
Incidence in the United States
Data suggest that 2-6 cases of PPHN occur per 1000 live births.
Age predilection
By definition, PPHN is a disorder of newborn infants. However, pulmonary hypertension may complicate the course of older infants with chronic respiratory insufficiency due to bronchopulmonary dysplasia.
Patient History
Although persistent pulmonary hypertension of the newborn is often associated with perinatal distress, such as asphyxia, low Apgar scores, meconium staining, and other factors, idiopathic persistent pulmonary hypertension of the newborn can present without signs of acute perinatal distress. Marked lability in oxygenation is frequently part of the clinical history.
Meconium aspiration. Serial radiographs in a newborn with uncomplicated meconium aspiration. Radiograph obtained shortly after birth shows ill-defined, predominantly perihilar opacities in the lungs; these are more severe on the right than on the left. The lungs are hyperexpanded. The neonate's heart size is within normal limits. The abnormalities on the initial chest radiograph, aside from the presence of an endotracheal tube and an umbilical artery catheter, are identical to those seen in severe cases of transient tachypnea of the newborn. Approximately 13% of all live births are complicated by meconium-stained fluid, but only 5% of infants who have this complication subsequently develop meconium aspiration syndrome. Although the traditional belief is that aspiration occurs with the first breath after birth, in severely affected infants, aspiration most likely occurs in utero. Therefore, perinatal distress or meconium staining of the amniotic fluid may be part of the patient's antenatal history.
Physical Examination
Persistent pulmonary hypertension of the newborn (PPHN) most typically affects infants who are phenotypically normal, although the syndrome occurs with higher frequency in newborns with Down syndrome. Upon initial examination, the primary finding is cyanosis, which is usually associated with tachypnea and respiratory distress. (Respiratory distress and cyanosis typically occur within 6-12 hours of birth.) Cardiac examination may reveal a loud, single S2 sound or a harsh systolic murmur secondary to tricuspid regurgitation. The patient may have evidence of poor cardiac function and perfusion.
Differential Diagnosis
The differential diagnosis for persistent pulmonary hypertension of the newborn (PPHN) includes the following: Congenital Diaphragmatic Hernia Meconium Aspiration Syndrome Partial Anomalous Pulmonary Venous Connection Pneumonia Pneumothorax Pulmonary Atresia With Intact Ventricular Septum Pulmonary Hypoplasia
Pulmonary Sequestration Respiratory Distress Syndrome Sepsis Other problems to be considered include the following: Alveolar capillary dysplasia Surfactant protein B deficiency Total anomalous pulmonary venous connection Transposition of the great arteries Tricuspid atresia
Laboratory Studies
The following studies are indicated in persistent pulmonary hypertension of the newborn (PPHN):
Serum electrolytes
Monitor serum electrolyte and glucose levels initially and frequently. In particular, maintaining glucose and ionized calcium levels within the reference ranges is important, because hypoglycemia and hypocalcemia tend to worsen PPHN. Calcium is a critical cofactor for NO synthase activity.
Radiography
Chest radiography is useful in determining whether underlying parenchymal lung disease (eg, meconium aspiration syndrome, pneumonia, surfactant deficiency) is present. Chest radiography also assists in excluding underlying disorders, such as congenital diaphragmatic hernia. In newborns with idiopathic persistent pulmonary hypertension of the newborn (PPHN), the lung fields appear clear, with decreased vascular markings. Heart size is typically normal or slightly enlarged in infants with PPHN.
Echocardiography
Echocardiography is necessary to exclude cyanotic congenital heart disease. Defining the anatomy of the pulmonary veins can be extremely difficult if extrapulmonary right-to-left shunting of blood is present. Echocardiography can be used to determine if right-to-left shunting of blood across the ductus arteriosus and/or foramen ovale is present. A skilled ultrasonographer can use the peak velocity of the regurgitant flow across the tricuspid valve to calculate right ventricular systolic pressures and, thus, estimate right-sided vascular pressures. Echocardiology is needed before therapy with inhaled nitric oxide (iNO) is begun. The image allows the clinician to rule out left-sided obstructive lesions, such as an interrupted aortic arch, a hypoplastic left ventricle, and critical aortic stenosis. These lesions require right-to-left shunting through the ductus to maintain systemic perfusion and, therefore, are contraindications to iNO treatment. Although right-to-left shunting at the patent ductus arteriosus and patent foramen ovale is typical for persistent pulmonary hypertension of the newborn, predominant right-to-left shunting at the patent ductus arteriosus but left-to-right shunt at the patent foramen ovale may help to identify the important role played by left ventricular dysfunction in the underlying pathophysiology. This must be corrected before considering the use of pulmonary vasodilators.
Ultrasonography
Perform cranial ultrasonography if ECMO is considered in a newborn, to evaluate for intraventricular bleeding and for peripheral areas of hemorrhage or infarct. Doppler flow studies can be a helpful adjunct in determining whether a nonhemorrhagic infarct is present.
Other Tests
Pulse oximetry
Continuous pulse oximetry is extremely valuable in the ongoing treatment of the newborn with persistent pulmonary hypertension of the newborn (PPHN), allowing the caregiver to assess the patient's oxygen saturation over time and to determine whether oxygen delivery at the tissue level is adequate. Oximeter probes can be placed on preductal (right hand) and postductal (right or left foot) sites to assess for right-to-left shunt at the level of the ductus arteriosus. Remember that sites on the left hand should be avoided because it may be preductal or postductal. Although it is a useful indicator of PPHN when present, a ductus-level shunt is frequently absent.
Cardiac catheterization
In rare cases, echocardiographic findings are not definitive, and cardiac catheterization may be necessary to exclude congenital heart disease, particularly anomalous pulmonary venous return.
Inotropic drugs
Inotropic support with dopamine, dobutamine, and/or milrinone is frequently helpful in maintaining adequate cardiac output and systemic blood pressure while avoiding excessive volume administration. Although dopamine is frequently used as a first-line agent, other agents, such as dobutamine and milrinone, are helpful when myocardial contractility is poor. Place a central venous catheter into the umbilical or other vein to allow for the administration of inotropic agents or hypertonic solutions (eg, calcium gluconate solution). Avoid catheter placement into the jugular vessels; save these vessels for extracorporeal support, if needed.
Surfactant administration
Parenchymal lung disease of the term or near-term newborn is often associated with surfactant deficiency, inactivation, or both. Data from small studies suggest that a benefit occurs after surfactant is administered to the newborn with meconium aspiration syndrome. In a large, multicenter study, the administration of surfactant reduced the need for extracorporeal support and appeared to be most effective early in the course of disease. The reduced need for ECMO was most apparent in newborns with primary diagnoses of meconium aspiration syndrome or sepsis.
High-frequency ventilation
High-frequency ventilation (HFV) is another important modality if a newborn has underlying parenchymal lung disease with low lung volumes. This modality is best used in a center with physicians who are experienced in achieving and maintaining optimal lung distension. The response to HFV can be rapid, and care must be taken to prevent hypocarbia and lung overdistension.
Mechanical ventilation
Endotracheal intubation and mechanical ventilation are almost always necessary for the newborn with persistent pulmonary hypertension of the newborn (PPHN). The goal of mechanical ventilation should be to maintain normal functional residual capacity (FRC) by recruiting areas of atelectasis, as well as to avoid overexpansion. Adjust ventilator settings to maintain normal expansion (ie, of approximately 9 ribs) on chest radiography. Monitoring of tidal volume and of pulmonary mechanics is frequently helpful in preventing overexpansion, which can elevate PVR and aggravate right-to-left shunting. In newborns with severe airspace disease who require high peak inspiratory pressures (ie, >30 cm water) or mean airway pressures (>15 cm water), consider HFV to reduce barotraumas and associated air leak syndrome. When HFV is used, the goal should still be to optimize lung expansion and FRC and to avoid overdistension. Determine the exact mechanical ventilation strategy on the basis of the underlying lung disease. For instance, newborns with clinically significant airspace disease due to pneumonia or respiratory distress syndrome likely require airway pressures higher than those needed for patients with idiopathic "black lung" PPHN. Likewise, newborns with clinically significant airspace disease are most likely to respond to other lung recruitment strategies, such as surfactant administration and/or high-frequency oscillatory ventilation. A frequent concern is determining the target arterial PaO 2 level. Although hyperoxic ventilation continues to be a mainstay in the treatment of PPHN, surprisingly little is known about what oxygen concentrations maximize benefits and minimize risks. Levels of 50 mm Hg or more typically provide for adequate oxygen delivery. Aiming for high PaO 2 concentrations may lead to increased ventilator support and barotrauma. Further, the use of extreme hyperoxia in PPHN management may be toxic to the developing lung owing to the formation of reactive oxygen species. Because of their lability and ability to fight the ventilator, newborns with persistent pulmonary hypertension of the newborn nearly always require sedation. The author's practice is to use fentanyl (often in combination with a benzodiazepine) because it tends to decrease the sympathetic response to pain and noxious stimuli.
Induced paralysis
The use of paralytic agents is highly controversial and is typically reserved for newborns who cannot be treated with sedatives alone. Be aware that paralysis, in particular with pancuronium, may promote atelectasis of dependent lung regions and promote ventilationperfusion mismatch. A review of 385 newborns with persistent pulmonary hypertension of the newborn by Walsh-Sukys and colleagues suggests that paralysis may be associated with an increased risk of death. [6] Another report indicates that prolonged administration of pancuronium during the neonatal period is associated with sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.
Medications
Sedation and analgesia with opioids are often necessary to achieve adequate mechanical ventilation in patients with persistent pulmonary hypertension of the newborn (PPHN). Muscle paralysis may be used for the same purpose; as previously mentioned, however, this method is controversial, because adverse circulatory effects and alveolar collapse in dependent regions of the lung may develop. The administration of a surfactant may be helpful if parenchymal disease is present. Cardiac output is maintained with the use of inotropic agents and with judicious volume replacement. Maintaining a normal or alkaline pH level with infusions of sodium bicarbonate may decrease pulmonary-artery pressure and improve oxygenation. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that reduces the need for invasive therapies, such as ECMO.
Feeding
Newborns recovering from persistent pulmonary hypertension of the newborn often feed poorly for several days or weeks. Nasogastric (NG) feeding is frequently required to support the newborn until oral feeding is established. Speech therapists may be helpful in reestablishing normal patterns of feeding.
Follow-Up Care
Because of the high risk of neurodevelopmental impairment and sensorineural hearing loss, infants should be monitored closely for the first 2 years of life, preferably in a specialty follow-up clinic for developmental follow-up care. Recommend complete screening before pediatric patients enter school, to determine if they have any subtle deficits that may predispose them to learning disabilities. Reassess the infant's hearing when he or she is aged 6 months and again as the results indicate. Late sensorineural hearing loss has been reported in a high percentage of patients.